1. Technical Field
The present invention is directed to novel platinum (IV) complexes having antitumor or antineoplastic activity. More particularly, the present invention relates to substantially isomerically pure tetrahalo, preferably tetrachloro, (1,2-diaminocyclohexane) platinum (IV) compounds and their use as effective antitumor agents.
2. Description of the Prior Art
Various platinum coordination compounds and their use as antitumor agents are known. Rosenberg et al (U.S. Pat. No. 4,177,263) discloses several platinum complexes and a method of treating malignant tumors by the parenteral administration of platinum complexes including a cis-tetrachlorodiammine platinum (IV) complex. Belgium Pat. No. 886,929 (Chem. Abstracts 95, 181, 198a) discloses di- and tetrahalo (1,1-diaminomethylcycloalkane) Pt (II) and Pt (IV) compounds as antitumor agents. German Offen. DE No. 3,207,472 discloses cis-dichloro trans-dihydroxy [1-amino-2-(aminomethyl)-3,3,5-trimethylcyclopentane]platinum (IV) and related structures for the treatment of cancer. U.S. Pat. No. 360,424 and German Pat. No. 158,777 describe organoplatinum complexes and their preparation. U.S. Pat. No. 4,200,583 discloses cis-platinum (II) coordinates 1,2-diaminocyclohexane (cis-, trans-l and trans-d) exhibiting anti-tumor activity. Hill et al, Anticancer Research 2, 173, (1982), presents a recent review of organoplatinum complexes as antitumor agents. Schwartz et al, Cancer Treatment Reports, 61, 1519 (1977), discloses the synthesis, water solubility and antileukemic activity of tetrachloro (1,2-diaminocyclohexane) platinum (IV) complex (NSC 276017). It should be noted, however, that the Pt(IV) complex of Schwartz et al, supra, designated NSC 276017, is an isomeric mixture [cis and trans (d and l)] of the tetrachloro (1,2-diaminocyclohexane) platinum (IV) complex and not an isomerically pure preparation. Furthermore, as noted by Hall et al, Wadley med. Bulletin, 7 (1):231 (1977), wherein studies relating to antileukemic activity of several platinum (IV) analogs including a tetrachloro (1,2-diaminocyclohexane) derivative have been described, "platinum (IV) compounds were, in general, less active than the corresponding platinum (II) species". Since Hall et al, supra, clearly states that "All diamines are in the `trans` configuration", it is clear that the compounds tested by Hall et al, supra, are not isomerically pure complexes but a mixture of optical isomers, possibly cis. In any event, an isomerically pure preparation of Pt(IV) complex could not have been the object of Hall et al's study since methods to detect an isomeric mixture simply did not exist at that time. Furthermore, Hall et al reached the conclusion that "- - - the activity of most platinum II analogs were lowered by oxidation to a plus four state".
It may be noted in this connection that Kidani et al., Gann, 67, 921, (1976) reported differences in antitumor activity (leukemia L1210) when testing pure isomers of dichloro (1,2-diaminocyclohexane) platinum (II) complex: the trans (1) isomer showing the highest activity, the trans (d) isomer possessing intermediate activity while the cis was the least active.
Later, the same authors reported on the antitumor activity (sarcoma-180, ascites form) for the same compounds and stated that in this test-system the cis isomer was more efficacious than the corresponding trans isomers. See J. Med. Chem., 21: 1315, (1978). Observation on these and related compounds can be found summarized in Structure-Activity Relationships of Antitumor Agents, 59 (1983).
In light of the generally held view among those skilled in the art that Pt(IV) analogs exhibit relatively poor antineoplastic activity compared to Pt(II) coordination compounds, the focus of research and screening of anti-cancer drugs has centered mostly in the development of Pt(II) complexes. In fact, the remarkable success of cisplatin, cis-diamminedichloroplatinum (II), as an efficacious drug in the treatment of testicular and other cancers has given impetus to the testing of a wide variety of organoplatinum compounds, particularly of the Pt (II) variety.
It should be noted, however, that the usefulness of cisplatin has been limited by its lack of effectiveness against cisplatin-resistant tumor cells and due to its toxicities, mainly nephrotoxicity, nausea and vomiting, myelosuppression, ototoxicity, peripheral neuropathy, allergic reactions, and electrolyte imbalances, including hypomagnesia. Because of these limitations, there has been a concerted effort to develop platinum complexes generally having the following properties: comparable or superior activity to cisplatin in a variety of experimental tumor models, lack of cross-resistance with cisplatin, lesser toxicity than cisplatin, good water solubility, good stability in aqueous solution, good purity and chemical homogeneity. As noted herein above, the development of Pt(IV) complexes generally had been ignored because of early work by Hall et al, supra, and others concluding that Platinum IV complexes were usually less active than their corresponding Platinum II complexes. Furthermore, one of the most recalcitrant problems in the clinical treatment of cancer is the problem of drug resistance. A physician needs to be able to switch from one drug or combination of drugs to another drug (or combination of drugs) to eradicate cells which no longer respond to the first treatment. Based on the well-accepted hypothesis of tumor cell heterogeneity, it is not unexpected that the initial treatment may produce a clinical response by killing a select population of sensitive cells. However, if the tumor is not completely eradicated, it is quite possible for tumor cells with reduced sensitivity to the original treatment to repopulate the tumor. In such circumstances the use of other treatment modalities, e.g. other chemotherapeutic agents, radiation therapy and the like, is usually necessary.
The Applicants have now surprisingly discovered that certain substantially isomerically pure Pt (IV) complexes not only have potent regressive activity against malignant tumors but also have efficacy against a subline of tumor cells with acquired resistance to cisplatin.